Crystallization of diastereomeric salts

Chemical synthesis of racemates and subsequent resolution via crystallization of diastereomeric salts is employed in the preparation of rf-biotin and tocopherol (vitamins), dexchlorpheniramine (antihistaminic), levomepromazine (neuroleptic), levorphanol (analgesic), and naproxen (antiphlogistic), to note some examples4, threo-2-Amino-1 -(4-nitro-phenyl)-l,3-propanediol, an intermediate in the production of chloramphenicol, is resolved by crystallization with entrainment or via crystallization of the salt with camphorsulfonic acid4. Enzymatic resolutions are increasingly employed, normally via deacetylation of racemic acetates. This method has recently been used in the synthesis of carbacyclin derivatives5. 

D-Pantothenic acid is also traditionally produced by chemical processes which involve efficient but troublesome and costly crystallization of diastereomeric salts of pantoate and chiral amines. After lactonization of the isolated D-pantoate, d-pantolactone is reacted with / -alanine to give D-pantothenate. Because the monovalent salts of pantothenic acid are highly hygroscopic, conversion into the calcium salt is essential for convenient formulation. The third class of synthetic processes for optically active compounds makes use of biotechnology. For natural com-... 

There are two main routes for the production of D-amino acids chemical synthesis and enzymatic catalysis. As regards conventional chemical synthesis, unless asymmetrical starting compounds or catalysts are used, a mixture of the D- and L-stereoisomers is obtained in equal proportions. The racemic mixture is therefore optically inactive and the stereoisomers must be separated. The separation of the enantiomers by classical crystallization of diastereomeric salts is the most costly production step and in any case this method can only yield 50% of the desired enantiomer [3]. Enzymatic synthesis can solve the above problems, providing optical purity of the D-amino acid and a 100% yield, as well as mild, environment-friendly reaction conditions. 

Resolution of Carboxylic Acids. The enantiomers of 1-(1-naphthyl)ethylamine are used to resolve racemic carboxylic acids by selective crystallization of diastereomeric salts. For example, crystallization of racemic 3-bromobutyric acid with (R)-(+)-NEA followed by acidification of the diastereomeric salt afforded (S)-(+)-3-bromobutyric acid (eq 1). In the same manner, resolution with (5)-(-)-NEA yielded (R)-(-)-3-bromobutyric acid after liberation of the amine (eq 1). ... 

The resolution of racemic mixtures through fractional crystallization of diastereomeric salts is traditionally used for organic acids and bases (19). Often the separation requires multiple recrystallizations and, in addition to the desired product, results in the production of the unwanted isomer... 

Crystallization of diastereomeric salts obtained from an optically pure acid or an optically pure base is a classical method for the resolution of atropisomeric heterocycles presenting the complementary basic or acid functions. The method requires several trials to find the optimal resolving agent. Atropisomers bearing mono or diphosphine groups are separated using optically pure Pd(ll) complexes. Table 2 reports some selected examples. 

In synthetic operations, when a symmetrical (achiral) substrate is used, the product is racemic. Diastereomers are separated by physical methods, and the enantiomers of racemic amines are frequently obtained by fractional crystallization of diastereomeric salts formed with chiral acids. Although resolution of racemic amines by fractional crystallization of enantiomeric salts is still an important technique and the laboratory scale resolutions of many racemic amines have been reported , the separation of the enantiomers of chiral amines by chromatography " and their preparation by asymmetric synthesis using enzymes and other asymmetric catalysts have had extensive development during the... 

Enantiomerically pure compounds are usually obtained by asymmetric synthesis, crystallization of diastereomeric salts, kinetic resolution of racemic mixmres, or chiral chromatography. An interesting alternative to these methods is chiral discrimination of anions based on abiotic receptors. An ideal system could involve the translocation of a chiral... 

The enantiomers of the silanes 10 and 11 were obtained from the corresponding racemic mixtures rac-10 (for its synthesis see Scheme 4) and rac-11 (for its synthesis see Scheme 5) by a classical racemate resolution using the enantiomers of 0,0 -di-p-toluoyltartaric acid and l,l -binaphthyl-2,2 -diyl hydrogen phosphate, respectively, as resolving agents (for resolution by fractional crystallization of diastereomeric salts see Scheme The silanes (/f)-10, (5)-10, (/J)-ll and (S)- were isolated as almost... 

The specific rotation of amino acids in aqueous solution is strongly influenced by pH. It passes through a minimum in the neutral pH range and rises after addition of acids or bases (Table 1.3). There are various possible methods of separating the racemates which generally occur in amino acid synthesis (cf. 1.2.5). Selective crystallization of an over-saturated solution of racemate after seeding with an enantiomer is used, as is the fractioned crystallization of diastereomeric salts or other derivatives,... 

Under equilibrium condition, several thermodynamic relationships need to be satisfied during formation and crystallization of diastereomeric salts. Concepmally, it is easy to see that operating at a mother liquor concentration below the... 

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